This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. It was recently discovered that reduction of endogenous microtubule associated protein tau prevents the learning impairment usually seen in human amyloid precursor protein (hAPP) overexpressing mice, a mouse model of Alzheimer's disease. This prevention occurs despite a lack of tau pathology in the Alzheimer's mouse model and without a reduction in amyloid plaques in the brain of this mouse, implying that tau is downstream of amyloid beta pathology in this mouse model. This could occur through an active role of tau, via the formation of a toxic tau species, or a more passive role of tau, where removal of tau disrupts a key pathway in amyloid pathology. In order to explore the toxic tau hypothesis, we will prepare tau samples from hAPP and nontransgenic mice to compare the post-translational modifications in the tau samples by mass spectrometry. If a significant difference in post-translational modification of tau is seen, then biochemical methods will be used to explore the role of the modification, or modifications, in the amyloid pathology and behavioral deficits in the Alzheimer's disease mouse model.